Project Summary Type 1 diabetes mellitus (T1D) results from autoimmune-mediated destruction of the insulin-producing beta- cells within the pancreatic islets of Langerhans. Inflammatory events, infiltrating leukocytes, and destruction of islet beta-cells are key contributors to disease onset. We hypothesize that suppressing pro-inflammatory stimuli will reduce the disease causing mechanisms leading to T1D. Towards this goal, we propose to investigate the use of distinct glucocorticoid receptor (GR) agonists, which are not commercially available, to suppress inflammatory responses in pancreatic islets. Our published studies using mouse, rat, and human islets have indicated promising results, prompting a pursuit of in vivo pre-clinical proof of concept studies to address the basic biological processes contributing to autoimmunity and their suppression by engaging the GR. Two specific aims are proposed to investigate the efficacy and side effects of this innovative therapeutic approach. In Specific Aim 1, we will use the multiple low dose injection of streptozotocin model to investigate the in vivo effectiveness of novel glucocorticoid receptor agonists to suppress the acute inflammatory events in pancreatic islets that ultimately produce hyperglycemia. Behavioral and metabolic side effects will be monitored along with the primary immunological and physiological endpoints. In Specific Aim 2, we will investigate whether our GR agonist approach prevents diabetes in the non-obese diabetic (NOD) mouse, a model of chronic inflammation that displays spontaneous onset of classic autoimmune mechanisms relevant to human T1D. Understanding the principles and mechanisms underlying innovative glucocorticoid receptor agonist approaches have important implications for suppressing, treating, and curing autoimmune diseases.